Angiotensin II can act as a growth and differentiation factor for both smooth muscle and renal cells. While the biochemistry of the traditional effects of angiotensin II are understood in some detail, the biochemical actions of angiotensin II leading to growth regulation are far less clear. This grant adopts the hypothesis that to understand angiotensin II-mediated cell growth and differentiation, it is critical to study the intracellular signaling events initiated when angiotensin II binds to the AT 1 receptor. One such pathway is the Jak kinases and STAT transcription factors. My group has made an important contribution in describing the activation of this pathway by the AT 1 receptor. We propose to continue these studies by dissecting the binding of the At1 receptor with Jak2 kinase (Specific Aim 1) and with Stat1 (Specific Aim 2). We postulate that a critical region of the AT1 receptor is the signaling motif YIPP found in the carboxy terminal tail of the receptor, and that t his motif is necessary for angiotensin II- mediated Jak-STAT activation. Specific Aim 3 is to investigate the role of the YIPP motif in non-STAT signaling. The final portion of the grant is to study the role of the Jak-STATpathway in angiotensin II dependent cell proliferation.